ABSTRACT Red and processed meat consumption may play a role in lung cancer pathogenesis because of these meats' fat and carcinogen content.
We prospectively investigated whether meat type, cooking method, doneness level, and intake of specific meat mutagens and heme iron are associated with lung carcinoma.
Men (n = 278,380) and women (n = 189,596) from the National Institutes of Health-AARP Diet and Health Study with no history of cancer at baseline were monitored for 8 y. Diet was assessed with a 124-item food-frequency questionnaire. A meat-cooking module was used to estimate the intake of individual heterocyclic amines, benzo(a)pyrene, and heme iron. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs.
In a comparison of quintiles 5 with 1 (Q5vsQ1), a high intake of red meat was associated with an increased risk of lung carcinoma in both men (HR(Q5vsQ1): 1.22; 95% CI: 1.09, 1.38; P for trend = 0.005) and women (HR(Q5vsQ1): 1.13; 95% CI: 0.97, 1.32; P for trend = 0.05). A high intake of processed meat increased the risk only in men (HR(Q5vsQ1): 1.23; 95% CI: 1.10, 1.37; P for trend = 0.003). In an analysis stratified by smoking status, we observed a tendency for an increased risk with red meat intake in never smoking men and women; however, the risks were not statistically significant. In a comparison of tertiles 3 and 1 (T3vsT1), the risk of lung carcinoma was associated with intake of well-/very-well-done meat (HR(T3vsT1): 1.20; 95% CI: 1.07, 1.35; P for trend = 0.002) and the intake of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (HR(Q5vsQ1): 1.20; 95% CI: 1.04, 1.38; P for trend = 0.04) in men. Heme iron intake increased the risk of lung carcinoma in both men (HR(Q5vsQ1): 1.25; 95% CI: 1.07, 1.45; P for trend = 0.02) and women (HR(Q5vsQ1): 1.18; 95% CI: 0.99, 1.42; P for trend = 0.002).
We observed a moderate association between meat consumption and lung carcinoma, which might be explained by heme iron intake, high-temperature cooking, and associated mutagens.

[Show abstract][Hide abstract]ABSTRACT: Compelling evidence for naturally occurring immunosurveillance against malignancies informs and justifies some current approaches toward cancer immunotherapy. However, some types of immune reactions have also been shown to facilitate tumor progression. For example, our previous studies showed that although experimental tumor growth is enhanced by low levels of circulating antibodies directed against the nonhuman sialic acid N-glycolyl-neuraminic acid (Neu5Gc), which accumulates in human tumors, growth could be inhibited by anti-Neu5Gc antibodies from a different source, in a different model. However, it remains generally unclear whether the immune responses that mediate cancer immunosurveillance vs. those responsible for inflammatory facilitation are qualitatively and/or quantitatively distinct. Here, we address this question using multiple murine tumor growth models in which polyclonal antibodies against tumor antigens, such as Neu5Gc, can alter tumor progression. We found that although growth was stimulated at low antibody doses, it was inhibited by high doses, over a linear and remarkably narrow range, defining an immune response curve (IRC; i.e., inverse hormesis). Moreover, modulation of immune responses against the tumor by altering antibody avidity or by enhancing innate immunity shifted the IRC in the appropriate direction. Thus, the dualistic role of immunosurveillance vs. inflammation in modulating tumor progression can be quantitatively distinguished in multiple model systems, and can occur over a remarkably narrow range. Similar findings were made in a human tumor xenograft model using a narrow range of doses of a monoclonal antibody currently in clinical use. These findings may have implications for the etiology, prevention, and treatment of cancer.

Proceedings of the National Academy of Sciences 04/2014; DOI:10.1073/pnas.1209067111 · 9.81 Impact Factor

[Show abstract][Hide abstract]ABSTRACT: In 2007 the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) report judged that the evidence for an association between red and processed meat consumption and colorectal cancer was convincing. In addition, the effect of other animal products on cancer risk has been studied, and the WCRF/AICR report concluded that milk probably decreases the risk of colorectal cancer but diets high in calcium probably increase the risk of prostate cancer, whereas there was limited evidence for an association between milk and bladder cancer and insufficient evidence for other cancers. There are several potential mechanisms relating meat to cancer, including heterocyclic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, and heme iron. Although the evidence in favor of a link between red and processed meat and colorectal cancer is convincing, the relations with other cancers are unclear. In this review, we summarize cohort studies conducted by the National Cancer Institute on meat and dairy intake in relation to cancer since the 2007 WCRF/AICR report. We also report the findings of meta-analyses published since 2007.

[Show abstract][Hide abstract]ABSTRACT: This meta-analysis was to summarize the published studies about the association between red/processed meat consumption and the risk of lung cancer. 5 databases were systematically reviewed, and random-effect model was used to pool the study results and to assess dose-response relationships. Results shown that six cohort studies and twenty eight case-control studies were included in this meat-analysis. The pooled Risk Radios (RR) for total red meat and processed meat were 1.44 (95% CI, 1.29-1.61) and 1.23 (95% CI, 1.10-1.37), respectively. Dose-response analysis revealed that for every increment of 120 grams red meat per day the risk of lung cancer increases 35% and for every increment of 50 grams red meat per day the risk of lung cancer increases 20%. The present dose-response meta-analysis suggested that both red and processed meat consumption showed a positive effect on lung cancer risk.

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A prospective study of meat, cooking methods, meat mutagens, hemeiron, and lung cancer risks1–3Natas ˇa Tasevska, Rashmi Sinha, Victor Kipnis, Amy F Subar, Michael F Leitzmann, Albert R Hollenbeck, Neil E Caporaso,Arthur Schatzkin, and Amanda J CrossABSTRACTBackground: Red and processed meat consumption may play a rolein lung cancer pathogenesis because of these meats’ fat and carcin-ogen content.Objective: We prospectively investigated whether meat type, cook-ing method, doneness level, and intake of specific meat mutagensand heme iron are associated with lung carcinoma.Design: Men (n ¼ 278,380) and women (n ¼ 189,596) from theNational Institutes of Health–AARP Diet and Health Study with nohistory of cancer at baseline were monitored for 8 y. Diet wasassessed with a 124-item food-frequency questionnaire. A meat-cooking module was used to estimate the intake of individual het-erocyclic amines, benzo(a)pyrene, and heme iron. Cox proportionalhazards regression was used to estimate hazard ratios (HRs) and95% CIs.Results: In a comparison of quintiles 5 with 1 (Q5vsQ1), a highintake of red meat was associated with an increased risk of lungcarcinoma in both men (HRQ5vsQ1: 1.22; 95% CI: 1.09, 1.38; P fortrend ¼ 0.005) and women (HRQ5vsQ1: 1.13; 95% CI: 0.97, 1.32;P for trend ¼ 0.05). A high intake of processed meat increased therisk only in men (HRQ5vsQ1: 1.23; 95% CI: 1.10, 1.37; P for trend ¼0.003). In an analysis stratified by smoking status, we observeda tendency for an increased risk with red meat intake in neversmoking men and women; however, the risks were not statisticallysignificant. In a comparison of tertiles 3 and 1 (T3vsT1), the risk oflung carcinoma was associated with intake of well-/very-well-donemeat (HRT3vsT1: 1.20; 95% CI: 1.07, 1.35; P for trend ¼ 0.002)and the intake of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline(HRQ5vsQ1: 1.20; 95% CI: 1.04, 1.38; P for trend ¼ 0.04) in men.Heme iron intake increased the risk of lung carcinoma in both men(HRQ5vsQ1: 1.25; 95% CI: 1.07, 1.45; P for trend ¼ 0.02) and women(HRQ5vsQ1: 1.18; 95% CI: 0.99, 1.42; P for trend ¼ 0.002).Conclusion: We observed a moderate association between meatconsumption and lung carcinoma, which might be explained byheme iron intake, high-temperature cooking, and associated muta-gens. Am J Clin Nutr 2009;89:1884–94.INTRODUCTIONLung cancer is the leading cause of cancer death worldwide(1). Smoking is by far the most important risk factor for lungcancer, to which 85% of all cases can be attributed (2); however,diet may also play a role.A recent notable review of the evidence on diet and cancerconcluded that fruit and foods containing carotenoids areprobable protective factors for lung cancer, and there is limitedsuggestive evidence that nonstarchy vegetables and foods con-taining selenium and quercetin may be protective. Meat and fat,however, may be risk factors for lung cancer (2).Red and processed meat intakes have been hypothesized toplay a role in carcinogenesis because of these meats’ fat content,the carcinogens produced during high-temperature cooking (3–6)and preservation (7, 8), and the endogenous formation of mu-tagens from heme present in meat (9). Many case-control (6, 10–21) and cohort (22–26) studies have investigated the associationbetween meat intake and lung cancer, with inconclusive find-ings. However, most previous studies were based on limiteddietary data. Detailed information on meat cooking was avail-able in only one case-control study (6) and in no cohort studies.Such data are essential to assess the carcinogenic potential ofdifferent types of meat and to elucidate possible mechanisms.In a recent analysis of multiple cancer sites in ’0.5 millionparticipants of the National Institutes of Health (NIH)–AARPDiet and Health Study, Cross et al (27) found an elevated risk oflung cancer for the highest compared with the lowest quintile ofred (1.20; 95% CI: 1.10, 1.31) and processed meat (1.16; 95%CI: 1.06, 1.26) intakes. In the present study, we extended theanalysis using detailed dietary data on meat cooking methodsand doneness level to further investigate the association between1From the Division of Cancer Epidemiology and Genetics, National Can-cer Institute, National Institutes of Health, Department of Health and HumanServices, Bethesda, MD (NT, RS, MFL, NEC, AS, and AJC); the BiometryResearch Group, Division of Cancer Prevention, National Cancer Institute,National Institutes of Health, Department of Health and Human Services,Bethesda, MD (VK); the Risk Factor Monitoring and Methods Branch,Applied Research Program, Division of Cancer Control and Population Sci-ences, National Cancer Institute, National Institutes of Health, Departmentof Health and Human Services, Bethesda, MD (AFS); and the AARP,Washington, DC (ARH).2Supported by the Intramural Research Program of the National CancerInstitute, National Institutes of Health, Department of Health and HumanServices.3Address correspondence to N Tasevska, Nutritional Epidemiology Branch,Division of Cancer Epidemiology and Genetics, National Cancer Institute,6120 Executive Boulevard, EPS/3032, Bethesda, MD, 20892-7242. E-mail:tasevskan@mail.nih.gov.Received November 24, 2008. Accepted for publication March 3, 2009.First published online April 15, 2009; doi: 10.3945/ajcn.2008.27272.1884Am J Clin Nutr 2009;89:1884–94. Printed in USA. ? 2009 American Society for Nutrition by guest on May 16, 2011www.ajcn.orgDownloaded from

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meat and lung cancer. The detailed questionnaire enabled us toassess intakes of different types of meat, heme iron, and meatmutagens, including heterocyclic amines (HCAs) and the poly-cyclic aromatic hydrocarbon (PAH) benzo(a)pyrene (B(a)P), andan overall meat-mutagenic activity index. The large sample sizeallowed us to study the effect of meat by smoking strata andhistologic subtypes of lung cancer.SUBJECTS AND METHODSStudy populationThe NIH-AARP Diet and Health Study is a prospective cohortstudyofmenandwomenaged50–71yfrom8statesintheUnitedStates (California, Florida, Louisiana, New Jersey, North Caro-lina, Michigan, Georgia, and Pennsylvania). Recruitment beganin 1995 when a self-administered baseline questionnaire, in-cluding questions on demographic characteristics, personal andfamily medical history, diet, and other lifestyle factors, wasmailed to 3.5 million members of the AARP. The questionnairewas returned by 617,119 members, of whom 567,169 completedthe questionnaire satisfactorily. Further details of the recruitmentand the study design are reported elsewhere (28). The NIH-AARP Diet and Health Study was approved by the SpecialStudies Institutional Review Board of the US National CancerInstitute, and written informed consent was obtained from allparticipants by means of completing the baseline questionnaire.Cohort follow-up and case ascertainmentCohort members werefollowed annuallyfor change ofaddressby using the US Postal Service and the Maximum Change ofAddress database (MaxCoA; maintained by Anchor Computer).Additional information on change of address was received di-rectly from participants who reported address changes whenresponding to a study mailing, such as follow-up questionnairesor newsletters. Follow-up was calculated from baseline (1995–1996) until censoring at the end of 2003 or when the participantmoved out of one of the study areas, had a cancer diagnosis, ordied, whichever came first. In addition, we expanded our cancerregistry ascertainment area by 3 states (Arizona, Nevada, andTexas) to capture cancer cases occurring among participants whomoved to those states during follow-up. Approximately 4% ofparticipants were lost to follow-up. Vital status was ascertainedbyannuallinkagetotheUSSocialSecurityAdministrationDeathMaster File and follow-up searches of the National Death Index(NDI). Cancer cases were identified by linkage to 11 state cancerregistries and the NDI Plus. The state cancer registry databasesare estimated to be ?90% complete within 2 y of cancer in-cidence (29). For this analysis, we included all incident cases ofprimary epithelial lung and bronchial carcinoma [InternationalClassification of Diseases (ICD) codes 34.0 to 34.9] (30). Byhistologic subtype, the cases were grouped as small cell (8002,8041, 8042, 8043, 8044, and 8045), adenocarcinoma (bron-choalveolar: 8250, 8251, 8253, and 8254; and other: 8140, 8200,8231, 8255, 8260, 8290, 8310, 8323, 8430, 8480, 8481, 8490,8550, and 8574), squamous (8050, 8070, 8071, 8072, 8073,8074, 8075, and 8084), undifferentiated/large cell (8012, 8014,8020, 8021, 8022, 8031, and 8032), other or not otherwisespecified carcinoma (NOS) (8010, 8011, 8033, 8046, 8123,8560, and 8562), sarcoma (8800, 8801, 8830, 8890, 8972, 8980,9120), neuroendocrine (8246), and carcinoid (8240, 8244, and8249) tumors. We excluded a total of 659 cases of sarcoma andneuroendocrine and carcinoid tumors, because of their poten-tially different etiologies.Dietary assessmentA self-administered semiquantitative food-frequency ques-tionnaire (FFQ) with 124 food items (31) was sent at baseline toassess the participants’ usual diet over the previous 12 mo. TheFFQ was calibrated in a substudy of 1415 participants by using 2nonconsecutive 24-h dietary recalls (28). The correlations be-tween red meat intake from the FFQ and the 24-h dietary recalls,adjusted for random within-person error, were 0.62 in men and0.70 in women.A second FFQ was mailed within 6 mo of the baseline ques-tionnaire to all participants, of whom 332,913 responded. Thesecond FFQ contained a meat-cooking module with detailedquestions on cooking methods and the doneness level of certainmeats (ie, hamburgers, steak, bacon, and chicken). We used theCHARRED-database (http://charred.cancer.gov/) along with themeat-cooking module to estimate the intake of HCAs—2-amino-3,4,8-trimethylimidazo[4,5-f ]quinoxaline (DiMeIQx); 2-amino-3,8-dimethylimidazo[4,5-f ]quinoxalineamino-1-methyl-6-phenylimidazo[4,5-b]pyridine(PhIP)—,thePAH[B(a)P],and the overall mutagenic activity (revertant colonies pergram of daily meat intake) (32). The CHARRED database wasdeveloped from laboratory analyzed values of HCAs, B(a)P, andoverallmutagenicactivityfrom’120 categoriesof meatsamplesprepared by different cooking methods with varying donenesslevels(4,5,33,34).HemeironwasestimatedbyusingpreliminarydatafromaNationalCancerInstitutedatabasebasedonmeasuredvalues from meat samples (33) for all meats with known cookinginformation from the meat-cooking module and from pork chops,sausages, and hotdogs. The relative validity of the meat cookingmodule at estimating the intake of HCAs was assessed in 165healthy participants; the de-attenuated correlation coefficientswere 0.60 and 0.36 for MeIQx and PhIP, respectively (35).(MeIQx);and2-Statistical analysisWe excluded subjects with duplicate questionnaires (n ¼ 179),those who moved out of the study areas or died before baseline(n ¼ 582), thosewhowithdrew from the study (n ¼ 6), thosewhowereproxyresponders(n¼15,760),prevalentcasesofanycancerexcept nonmelanoma skin cancer (n ¼ 51,193), those who re-portedend-stagerenaldiseaseatbaseline(n¼997),subjectswhodied before the questionnairewas received(n ¼ 3876), thosewithzero person-years (n ¼ 11), and those who provided no in-formationonsmoking(n¼19,096).Wefurtherexcludedsubjectswith implausible energy intakes (beyond twice the interquartilerange of sex-specific Box-Cox transformed intake) (n ¼ 3897).Thesameexclusioncriteriawasappliedforthoseattheupperendof the intake distribution for energy-adjusted saturated fat (n ¼491), fruit (n ¼ 744), and vegetable servings (n ¼ 1702). In theanalyses with meat as a continuous variable, we also excludedsubjectsattheupperendforred,white,processed,orunprocessedmeat intake after Box-Cox transformation (n ¼ 2790). Our finalbaseline cohort consisted of 278,380 men and 189,596 women.MEAT INTAKE AND LUNG CANCER1885 by guest on May 16, 2011www.ajcn.orgDownloaded from

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Completed meat-cooking modules were available for 168,879men and 121,493 women.Sex-specific Cox proportional hazards regression models, withage as the underlying time metric, were used to estimate hazardratios (HRs) and 95% CIs by sex. The baseline meat and meatmutagen variables were categorized into quintiles based on sex-specificcutoffswithinthecohort,whereasmeatintakebycookingmethodswascategorizedintotertilesbecauseofthesmallerrangesofintake.Aftertestingforaninteractionbetweensexandredmeatintake for all the covariates, we found several statistically sig-nificant interactions; therefore, all findings are presented by sex.Themultivariablemodelsweredevelopedbyindividuallyenteringpotentialconfoundersintoabasicmodelwithage,energy,andredand white meat. Variables remained in the model if they wereestablished risk factors for lung cancer (race, education, andsmoking) or if they changed the risk estimate by ?10% or wereconsidered potential risk factors for lung carcinoma (body massindex,physicalactivity,andfruit,vegetable,alcohol,andsaturatedfatintakes).Definitionofthecovariatesarelistedinthetables.Alldietaryvariables,exceptalcohol,wereenergyadjustedbyusingthenutrient density method. Because of the high proportion of zerovaluesforalcohol,wemodeledalcoholintakeusing2variables:1)abinaryvariablethatequalled1ifalcoholintakewas,0.09g/dorequalled 0 otherwise and 2) a continuous variable where a valueof0wasimputedinparticipantswithalcoholintake,0.09g/d.Totest for heterogeneity, we used Cochran’s Q statistics (36).SmokingThe baseline questionnaire queried about whether participantshadsmoked.100cigarettesduringtheirlife(eversmokers),aboutsmokingintensity(cigarettessmokedperday),whethertheywerecurrently smoking, and years since smoking cessation for formersmokers. Those who reported quitting within the past year wereconsideredcurrentsmokers.Inthemainanalyses,weuseda9-levelsmoking variable. We conducted a stratified analyses by smokingstatus,inwhich,becauseoffewcasesamongneversmokers,meatwasexaminedasacontinuousvariableafterensuringthelinearityof the relation between meat and lung carcinoma by a non-parametric method with restricted cubic splines (37). The HRs onthe continuous scalewere calculated forthe increase in therisk ofthe 90th compared with the 10th percentile of meat intake. To testfor interactions between meat intake and smoking status in theproportional hazards models, we fitted 3 models that includedcross-product terms between red and processed meat intake andsmoking,modeledwitheitherthe9-levelsmokingstatusvariable,the 5-level smoking status variable (never smokers, formersmokers who quit .10 y ago, former smokers who quit 5–10 yago, former smokers who quit 1–5 y ago, or former smokers whoquit ,1 y ago or were current smokers) additionally adjusted forthe 6-level smoking intensity variable (1–10, 11–20, 21–30, 31–40, 41–50, or 51–60 cigarettes/d) or with the 6-level smokingintensity variable additionally adjusted for the 5-level smokingstatus variable. We used a likelihood ratio test to compare theproportional hazards models with and without cross-productterms, to test their significance.Sensitivityanalysestofurtherinvestigatetheconfoundingeffectof smoking included the use of a 31-level smoking variable con-structedbycombiningsmokingstatus,smokingintensity,andtimesince quitting smoking, as well as investigating these 3 smokingvariables as separate covariates in the model. All analyseswere conducted by using SAS version 9.1. The P values for thestatistical tests were 2-tailed and were considered significant ata level of ,0.05.RESULTSAfter up to 8 y of follow-up in our cohort of 278,380 men and189,596 women, lung carcinoma was diagnosed in 4089 men andin 2272 women. Both men and women were more likely to behigh consumers of red meat if they were white, were younger,were less educated, were less physically active, smoked, and hada higher BMI (Table 1). Furthermore, those eating more redmeat were more likely to have a high intake of processed meat,saturated fat, and total energy, but were less likely to eat whitemeat, eat fruit and vegetables, drink alcohol, and take b-carotenesupplements.Men in the fifth quintile (Q5) of red and processed meat intakewere more likely to develop lung carcinoma than were those inthe first quintile (red meat: 1.22; 95% CI: 1.09, 1.38; P fortrend ¼ 0.005; processed meat: 1.23; 95% CI: 1.10, 1.37; P fortrend ¼ 0.003) (Table 2). Consumption of red meat in womenwas of borderline statistical significance with lung carcinomarisk (HRQ5vsQ1: 1.13; 95% CI: 0.97, 1.32; P for trend ¼ 0.05),whereas consumption of processed meat was not associated withrisk (HRQ5vsQ1: 1.00; 95% CI: 0.87, 1.15; P for trend ¼ 0.58).In the analyses by histologic subtype, the risk of squamous cellcarcinomawasincreasedinmeninthehighestquintileofred(1.34;95% CI: 1.04, 1.73; P for trend ¼ 0.02) and processed (1.39; 95%CI: 1.10, 1.75; P for trend ¼ 0.01) meat intake (Table 3). Inwomen, the most striking observation was an elevated risk ofsmall cell carcinoma for those in the highest quintile of red meatintake (HRQ5vsQ1: 1.74; 95% CI: 1.14, 2.66; P for trend ¼ 0.03).Yet, P values for heterogeneity among histologic subtypes werenot statistically significant for either men (red meat: P ¼ 0.52;processed meat: P ¼ 0.57) or women (red meat: P ¼ 0.11; pro-cessed meat: P ¼ 0.16).In an analysis stratified by smoking, none of the risk estimatesamongneversmokingmenorwomenwerestatisticallysignificant(Table 4). However, the HRs for red meat in never smoking menand women were of a similar magnitude compared with the esti-mates for the whole cohort (Table 2) (men: 1.19 compared with1.22; women: 1.21 compared with 1.13, respectively). The ob-served risk associated with processed meat intake in neversmoking men was, however, notably lower than in the non-stratified analysis (HR: 1.06 compared with 1.23). In men, pro-cessedmeatwasassociatedwithastatisticallysignificantelevatedrisk in current smokers (P for trend ¼ 0.008) and in formersmokers who quit 1–10 y ago (P for trend ¼ 0.001), whereas redmeat intake increased the risk in those who quit .10 y ago (P fortrend ¼ 0.003) (Table 4) and yielded borderline statistically sig-nificant risk estimate in current smokers (P for trend ¼ 0.09). Inwomen, none of the risk estimates were statistically significant.In models that included interactions between red and pro-cessed meat intake and smoking, we found no statistically sig-nificant interaction between meat intake and smoking in amultivariable model with interaction terms by a 9-level smokingvariable for either men (red meat: P ¼ 0.64; processed meat: P ¼0.39) or women (red meat: P ¼ 0.91; processed meat: P ¼ 0.87).Likewise, we found no statistically significant interaction in1886TASEVSKA ET AL by guest on May 16, 2011www.ajcn.orgDownloaded from